{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:16:32Z","timestamp":1792790192675,"version":"4.5.0"},"reference-count":138,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,7,24]],"date-time":"2021-07-24T00:00:00Z","timestamp":1627084800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of California, Natural Reserve System","award":["General Funding"],"award-info":[{"award-number":["General Funding"]}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["IOS-1655392"],"award-info":[{"award-number":["IOS-1655392"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Tetrodotoxin (TTX) is a potent neurotoxin that was first identified in pufferfish but has since been isolated from an array of taxa that host TTX-producing bacteria. However, determining its origin, ecosystem roles, and biomedical applications has challenged researchers for decades. Recognized as a poison and for its lethal effects on humans when ingested, TTX is primarily a powerful sodium channel inhibitor that targets voltage-gated sodium channels, including six of the nine mammalian isoforms. Although lethal doses for humans range from 1.5\u20132.0 mg TTX (blood level 9 ng\/mL), when it is administered at levels far below LD50, TTX exhibits therapeutic properties, especially to treat cancer-related pain, neuropathic pain, and visceral pain. Furthermore, TTX can potentially treat a variety of medical ailments, including heroin and cocaine withdrawal symptoms, spinal cord injuries, brain trauma, and some kinds of tumors. Here, we (i) describe the perplexing evolution and ecology of tetrodotoxin, (ii) review its mechanisms and modes of action, and (iii) offer an overview of the numerous ways it may be applied as a therapeutic. There is much to be explored in these three areas, and we offer ideas for future research that combine evolutionary biology with therapeutics. The TTX system holds great promise as a therapeutic and understanding the origin and chemical ecology of TTX as a poison will only improve its general benefit to humanity.<\/jats:p>","DOI":"10.3390\/toxins13080517","type":"journal-article","created":{"date-parts":[[2021,7,25]],"date-time":"2021-07-25T22:07:00Z","timestamp":1627250820000},"page":"517","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["From Poison to Promise: The Evolution of Tetrodotoxin and Its Potential as a Therapeutic"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3345-1361","authenticated-orcid":false,"given":"Gary M.","family":"Bucciarelli","sequence":"first","affiliation":[{"name":"Department of Ecology and Evolutionary Biology & UCLA La Kretz Center for California Conservation Science, Institute of the Environment and Sustainability, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maren","family":"Lechner","sequence":"additional","affiliation":[{"name":"Department of Ecology and Evolutionary Biology & UCLA La Kretz Center for California Conservation Science, Institute of the Environment and Sustainability, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey","family":"Fontes","sequence":"additional","affiliation":[{"name":"Natural Science Division, Pepperdine University, Malibu, CA 90263, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee B.","family":"Kats","sequence":"additional","affiliation":[{"name":"Natural Science Division, Pepperdine University, Malibu, CA 90263, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9049-5750","authenticated-orcid":false,"given":"Heather L.","family":"Eisthen","sequence":"additional","affiliation":[{"name":"Department of Integrative Biology, Michigan State University, East Lansing, MI 48824, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5795-9242","authenticated-orcid":false,"given":"H. Bradley","family":"Shaffer","sequence":"additional","affiliation":[{"name":"Department of Ecology and Evolutionary Biology & UCLA La Kretz Center for California Conservation Science, Institute of the Environment and Sustainability, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"693","DOI":"10.3390\/toxins6020693","article-title":"Tetrodotoxin: Chemistry, Toxicity, Source, Distribution and Detection","volume":"6","author":"Bane","year":"2014","journal-title":"Toxins"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"6384","DOI":"10.3390\/md13106384","article-title":"Tetrodotoxin, an Extremely Potent Marine Neurotoxin: Distribution, Toxicity, Origin and Therapeutical Uses","volume":"13","author":"Lago","year":"2015","journal-title":"Mar. 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